Long-term alcohol consumption progressively leads to multiple immune defects. Chronic alcoholics display lesions in both innate and adaptive immunity, and experience increased rates of bacterial and viral infection. Of particular interest, extended alcohol intake leads to abnormalities within the B cell compartment. In many alcohol abusers, total circulating B cells are depressed and Ab titers in response to vaccination are poor. In addition to humeral deficiency, regulation of B cell activity is disrupted leading to increased levels of serum Ig and the presence of autoantibodies. Taken together, it is clear that alcohol leads to impaired B cell function, and in turn, life-threatening infections. In order to understand better the extent of B cell dysfunction, and the means by which ethanol effects these changes, it is essential to utilize experimental models. A large number of studies have employed rodent models where ethanol is administered in liquid diets over short periods. Although a range of immune defects have been documented with this approach, these findings are best applied to abnormalities that appear after binge drinking in humans given the short duration of consumption and induction of the stress response. In order to better mimic the condition of chronic alcoholism, we have established a long-term murine model where ethanol is provided in drinking water. Using this system, we have found that months of ethanol intake result in loss of mature splenic B cells and diminished T cell-dependent (TD) antibody (Ab) responses. We have further discovered abnormalities in B cell maturation and lymphoid structure. Importantly, these defects develop without evidence of systemic stress. Using this model, proposed experiments will fully document the effects of ethanol on the B cell compartment, and the underlying mechanisms leading to humeral dysfunction. Studies in Aim 1 will test a number of hypotheses to explain the attrition of B cells after long-term ethanol intake, including defects in maturation, half-life, and production of supportive chemokines and cytokines. Aim 2 will ask whether ethanol induces cell autonomous lesions in B cells leading to abnormal activation and differentiation. Experiments in Aims 3 and 4 will assess the capacity of ethanol-consuming mice to produce Abs after immunization with T cell independent and TD antigens, respectively. Importantly, Aim 4 will thoroughly examine the effects of ethanol on T cell-driven B cell differentiation including affinity maturation, somatic mutation, generation of memory cells, and formation of long-lived plasma cells. Collectively, these studies will expand our understanding of humeral defects common to chronic alcoholics, and offer novel insights with which to fashion better therapies. [unreadable] [unreadable]